Radiosensitization by Hyperthermia: The Effects of Temperature, Sequence, and Time Interval in Cervical Cell Lines

Abstract

Cervical cancers are almost exclusively caused by an infection with the human papillomavirus (HPV). When patients suffering from cervical cancer have contraindications for chemoradiotherapy, radiotherapy combined with hyperthermia is a good treatment option. Radiation-induced DNA breaks can be repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Hyperthermia can temporarily inactivate homologous recombination. Therefore, combining radiotherapy with hyperthermia can result in the persistence of more fatal radiation-induced DNA breaks. However, there is no consensus on the optimal sequence of radiotherapy and hyperthermia and the optimal time interval between these modalities. Moreover, the temperature of hyperthermia and HPV-type may also be important in radiosensitization by hyperthermia. In this study we thoroughly investigated the impact of different temperatures (37–42 °C), and the sequence of and time interval (0 up to 4 h) between ionizing radiation and hyperthermia on HPV16+: SiHa, Caski; HPV18+: HeLa, C4I; and HPV−: C33A, HT3 cervical cancer cell lines. Our results demonstrate that a short time interval between treatments caused more unrepaired DNA damages and more cell kill, especially at higher temperatures. Although hyperthermia before ionizing radiation may result in slightly more DNA damage, the sequence between hyperthermia and ionizing radiation yielded similar effects on cell survival.

Mathematical model for the thermal enhancement of radiation response: thermodynamic approach

“…The most accepted hypothesis for the radiosensitising effect of HT assumes the heat-induced denaturation of repair proteins impairs the DNA repair process upon irradiation 12 , 33 , 44 . In the LQ-model hyperthermia mainly affects , which is supposedly related to repairable DNA single-strand breaks (SSB), and the HT-induced sensitisation is generally associated with inhibition of DNA repair 30 .…”

“…the Jung's model 40 , multiple-states models, Arrhenius models, biochemical models, stochastic models (reviewed in 41,42 ), among many others which include derivations of the LQ-model for RT 42,43 . For thermal-radiosensitisation using temperatures of 40-46 °C, there is a general agreement on a relevant role of DNA repair impairment by heat-induced protein denaturation in the processes of radiosensitisation 12,33,36,37,39,44 . The majority of previous approaches to model the combined efficacy of hyperthermia and radiation on mammalian cells have implemented the thermal effects in the LQ-model by proposing empirical temperature dependencies for the radiological parameters 43,45,46 , but the physical principles and the detailed mechanisms underlying this empirical dose-lowering concept are still elusive 44 .…”

“…Radiotherapy (RT) is supposedly a curative treatment modality, but the radiation dose required to eradicate all cancer cell subpopulations in a tumour can often not be applied due to severe acute or long-term side effects, which include radiation-induced tissue fibrosis and second malignancies 11 . Hyperthermia is known to be one of the most potent radiosensitisers [12][13][14][15][16] , meaning that less radiation is required to achieve the same local tumour cell kill, thereby reducing the adverse effects of radiation in the adjacent normal tissues, e.g. [17][18][19][20][21] .…”

Ethanol Enhances Hyperthermia-Induced Cell Death in Human Leukemia Cells

“…Hyperthermia is a realistic treatment option against cancer since temperatures in the range of 40–43 °C can reduce proliferation and induce cell death. It has been used for cancer treatment in combination with chemotherapy or radiotherapy [ 43 , 44 ]. There are several physical approaches for inducing hyperthermia, including electromagnetic radiation, ultrasound, hyperthermic perfusion, and conductive heating [ 10 ].…”

Hyperthermia-Based Anti-Cancer Treatments

“…Van den Tempel et al investigated the mechanisms driving hyperthermia-induced BRCA2 degradation, finding that BRCA2 degradation is evolutionarily conserved, BRCA2 stability is dependent on HSP90, ubiquitin might not be directly involved, and BRCA2 degradation might be modulated by oxidative stress and radical scavengers [ 5 ]. Mei et al investigated the impact of temperature (37–42 °C), sequence and time interval (0 up to 4 h) for ionizing radiation combined with hyperthermia on different HPV-positive and HPV-negative cervical cancer cell lines, demonstrating that shorter time intervals were associated with more unrepaired DNA damage and more tumour cell kill, especially at higher temperatures [ 6 ]. Hyperthermia at 42 °C was also demonstrated to have a marked potential in inducing an immunes response in an in vivo mouse model of colon adenocarcinoma, where intravenous administration of a human CCL3 variant carrying a single amino acid substitution after mild local hyperthermia treatment not only induced significant tumour growth inhibition but also inhibited metastasis [ 7 ].…”